PROJECT SUMMARY Lung cancer is the leading cause of cancer-related death worldwide. In contrast to adenocarcinoma, druggable molecular drivers have not been identi?ed in LUSC, and the current targeted agents for lung adenocarcinoma are largely ineffective. Moreover, the most active recently-approved non-speci?c agents (pemetrexed and bevucizumab) have been shown to be either less effective or overly toxic in patients with LUSC and therefore lack FDA approval for these patients. Therapeutically, LUSC is an orphan disease. Gradually, oncogenic alterations have been described in a proportion of LUSC, including SOX2 ampli?cation dysregulation of the KEAP-NFE2L2 pathway, aberrant PI3K pathway activity, FGFR1 ampli?cationand DDR2 mutation. While targeted therapeutics to some of these genes and pathways are in early-phase trials, none is yet clinically-available. Analysis of gene expression datasets from resected tumors has classi?ed histologic LUSC into four mRNA expres- sion subtypes, de?ned as classical (35-40% of LUSC), primitive, secretory and basal . The oncogenic drivers and potential cells of origin of tumors within these subtypes are likely different. However, the practical application of these expression subtypes in clinical care has not been determined. The lineage-speci?c transcription factor SOX2 is elevated in the classical subset. and in many tumor of the other subsets Using our published Sox2 over expression mouse, we have identi?ed Connective tissue growth factor (CTGF) as a potential therapeutic target downstream of Sox2. In this application, we propose to continue to develop targeted inhibition of CTGF to treat these patients. Aims include testing the effect of CTGF inhibition op proliferation and apoptosis in both preclinical and human tu- mor models and testing the effect of CTGF inhibition on chemotherapeutic sensitivity in both preclinical and human tumor models. We hope that completion of these aims will contribute further evidence that CTGF inhibition will help human squamous lung cancer patients.